title: Strategic nonmyeloablative conditioning: CD154:CD40 costimulatory blockade at primary bone marrow transplantation promotes engraftment for secondary bone marrow transplantation after engraftment failure.
abstract: There is an increased risk of failure of engraftment following nonmyeloablative conditioning. Sensitization resulting from failed bone marrow transplantation (BMT) remains a major challenge for secondary BMT. Approaches to allow successful retransplantation would have significant benefits for BMT candidates living with chronic diseases. We used a mouse model to investigate the effect of preparative regimens at primary BMT on outcome for secondary BMT. We found that conditioning with TBI or recipient T cell lymphodepletion at primary BMT did not promote successful secondary BMT. In striking contrast, successful secondary BMT could be achieved in mice conditioned with anti-CD154 costimulatory molecule blockade at first BMT. Blockade of CD154 alone or combined with T cell depletion inhibits generation of the humoral immune response after primary BMT, as evidenced by abrogation of production of anti-donor Abs. The humoral barrier is dominant in sensitization resulting from failed BMT, because almost all CFSE-labeled donor cells were killed at 0.5 and 3 h in sensitized recipients in in vivo cytotoxicity assay, reflecting Ab-mediated cytotoxicity. CD154:CD40 costimulatory blockade used at primary BMT promotes allogeneic engraftment in secondary BMT after engraftment failure at first BMT. The prevention of generation of anti-donor Abs at primary BMT is critical for successful secondary BMT.
authors.affiliation: Institute for Cellular Therapeutics, University of Louisville, Louisville, KY 40202, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Xu
authors.forename: Yiming
authors.initials: Y
authors.lastname: Huang
authors.forename: Paula M
authors.initials: PM
authors.lastname: Chilton
authors.forename: Lala-Rukh
authors.initials: LR
authors.lastname: Hussain
authors.forename: Michael K
authors.initials: MK
authors.lastname: Tanner
authors.forename: Jun
authors.initials: J
authors.lastname: Yan
authors.forename: Suzanne T
authors.initials: ST
authors.lastname: Ildstad
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000627:therapeutic use; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology; D016026:Bone Marrow Transplantation / Q000009:adverse effects / Q000276:immunology*; D019013:CD40 Antigens / Q000276:immunology*; D023201:CD40 Ligand / Q000276:immunology*; D002908:Chronic Disease; D006084:Graft Rejection / Q000276:immunology* / Q000517:prevention & control; D006085:Graft Survival / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D012086:Reoperation; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D014916:Whole-Body Irradiation
chemical_list: D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; D023201:CD40 Ligand